In eukaryotic cells, proteins destined for the cell surface or for the external milieu are first translocated into the endoplasmic reticulum (ER) where initial protein folding and modifications occur that are essential for the protein to attain its appropriate functional conformation prior to transit to the cell surface. It has long been known that mutations in the primary amino acid sequence can cause protein misfolding and contribute to disease pathogenesis. However, it is now becoming evident that in many cases disease states are not simply a result of protein loss of function, but rather frequently involve cellular processes that accommodate protein misfolding. Cells adapt to the accumulation of misfolded proteins in the ER by regulating several fundamental cellular processes including gene expression, mRNA translation, and protein degradation. We have now experienced significant breakthroughs in our understanding of how cells coordinate these adaptive responses. If adaptation is not adequate, cells enter an apoptotic death pathway. Recent studies reveal that protein misfolding results not only from gene mutations but also arises as a consequence of a variety of environmental insults including but not limited to altered metabolism, viral infection, oxidative stress, and hypercholesterolemia, as well as the altered ability to deal with these conditions that often occur during aging. Finally, many highly differentiated cell types, such as pancreatic beta cells and plasma cells, require signaling pathways to properly coordinate protein expression and secretion with the ER protein folding capacity. As we understand more about the adaptive and apoptotic responses to protein misfolding in the ER, it is evident that these events contribute to the pathology of numerous disease states. This conference will focus on recent advances in our understanding of the complexities of protein biosynthesis, folding, degradation, and cellular responses to the accumulation of misfolded proteins in the early secretory pathway as discovered through novel genetic, biochemical, and cell biological approaches. In addition, it will highlight studies on a broad collection of diseases that are caused by protein folding disorders and recent advances in approaches to prevent or correct misfolding. Identifying the mechanisms by which cells adapt and succumb to protein folding defects and the development of therapeutically useful inhibitors or activators of these processes are likely to have a tremendous impact on a variety of diseases including Alzheimer's disease, cardiovascular disease, diabetes, infectious diseases, cancer, and other diseases associated with the normal aging process. PUBLIC HEALTH RELEVANCE: It is now appreciated that protein misfolding in the endoplasmic reticulum contributes to a variety of human diseases ranging from metabolic and genetic disorders to cancer and heart disease, as well as to a number of conditions associated with normal aging processes. In fact studies indicate that the cellular folding machinery and quality control systems that oversee them decline with age, which further contributes to the problem. The goal of this FASEB meeting is to provide a venue for reporting cutting edge research findings and for promoting the free exchange of scientific information between investigators from multiple disciplines. This meeting will increase our understanding of the molecular mechanisms that regulate protein folding in the ER and should lead to the identification of critical targets for the prevention, diagnosis and/or treatment of human diseases.